The proteasome is a multi-subunit multi-catalytic protease complex present in the cytosol that is proposed to mediate cytosolic antigen processing to produce peptides for MHC class I presentation. LMP2 and 7 are regulated subunits that are present in a subset of proteasomes. They appear to alter proteasome activity to enhance cytosolic MHC I antigen (Ag) processing. They are constitutively expressed in some cell types, and expression is regulated by cytokines in other cell types. The investigators hypothesize that disruption of the MHC I Ag processing pathway in tumor cells results in escape from immune surveillance. The studies described in this application will evaluate the contribution of proteasomes, LMP2 and 7, in MHC I Ag processing and presentation to the immune system for generating antitumor immunity. Aim 1 will analyze the effects of novel dipeptide aldehyde proteasome inhibitors on conventional MHC I Ag processing. Aim 2 will use these inhibitors to assess the contribution of proteasomes to alternative mechanisms for processing of exogenous Ags. Aim 3 will test the hypothesis that LMP expression may be altered in tumor cells, resulting in tumor cell escape from immune surveillance. These studies should suggest mechanisms to enhance immune responses to tumors and facilitate immunotherapy of cancer.